Project 3: Neural mediators in the metabolic effects of Vertical Sleeve Gastrectomy

胃垂直袖状切除术后代谢影响的神经介质 摘要 关于吃什么和吃多少的决定是由一个复杂的通信网络控制的， 中枢神经系统和肠道，并涉及各种激素，代谢物和神经元反馈系统。减肥手术， 可以说是最有效的治疗肥胖及其并发症，改变这些反馈的各个方面， 系统，并导致大量的体重减轻和代谢改善。我们已经证明 营养素诱导的神经元激活（FOS）在特定的神经元亚群（降钙素受体; 孤束核（NTS）内的CALCR，NTS是一个中枢神经系统区域，对于整合外周神经系统至关重要。 信号和启动进食行为的变化，在特定的减肥手术后，垂直袖 胃切除术（VSG）。VSG是一种沿胃大弯沿着切除80%胃的手术， 产生了几个潜在的化学和机械传感信号，这些神经元响应，包括 营养素本身的水平，更大的胃压，或许多餐后肠道的数倍增加， 分泌肽本提案的总体目标是确定这些激活的 NTS神经元和这些神经元群被激活的机制。 在该计划项目的项目1和项目2中，我们生成了初步数据，表明不同的 NTS（LEPRb、CALCR和CCK）和PBN（GLP-1 R和CGRP）内的神经元群至关重要 用于调节进食和对毒素的反应，如通过条件性味觉厌恶所测量的。鉴于我们的 数据还表明，NTS内的CALCR是由VSG特异性激活的，VSG是我们的过度激活的。 一种假设是，肥胖损害了这些回路，减肥手术“修复”了这些回路，以减少进食， 导致体重减轻。为了验证这一假设，我们将结合使用遗传学和化学遗传学策略 与电生理学（使用神经生理学核心，NPC，Goforth），以确定相关的电路 在NTS（目标1）内，负责肥胖和减肥手术后喂养行为的变化，以及 在目标2中，我们将定义手术诱导的NTS激活的机制。

Neural mediators of the metabolic effects of vertical sleeve gastrectomy Abstract Decisions about what and how much to eat are regulated by a complex communication network between the CNS and gut and involve a variety of hormonal, metabolite, and neuronal feedback systems. Bariatric surgery, arguably the most effective treatment for obesity and its complications, alters every aspect of these feedback systems and results in substantial weight loss and metabolic improvements. We have demonstrated that nutrient-induced neuronal activation (FOS) is greater within a specific subset of neurons (calcitonin receptor; CALCR) within the nucleus of the solitary tract (NTS), a CNS region that is critical for integrating peripheral signals and initiating changes in feeding behavior, after a particular bariatric surgery, vertical sleeve gastrectomy (VSG). VSG, a procedure where 80% of the stomach along the greater curvature is removed, generates several potential chemo- and mechano-sensing signals that these neurons respond to including the levels of nutrients themselves, greater gastric pressure, or the several-fold increase in many postprandial gut- secreted peptides. The overall aim of this proposal is to determine the identity and function of these activated NTS neurons and the mechanism(s) by which these neuronal populations are activated. In projects 1&2 of this program project, we have generated preliminary data demonstrating that distinct populations of neurons within the NTS (LEPRb, CALCR, and CCK) and PBN (GLP-1R and CGRP) are critical for regulation of feeding and responses to toxins as measured by conditioned taste aversion. Given that our data also demonstrates that CALCR within the NTS are specifically activated by VSG, our over-arching hypothesis is that obesity impairs, and bariatric surgery “fixes” these circuits to reduce feeding and induce weight loss. To test this hypothesis, we will use genetic and chemogenetic strategies in combination with electrophysiology (using the neural physiology core, NPC, Goforth) to determine the relevant circuits within the NTS (Aim 1) responsible for changes in feeding behavior with obesity and after bariatric surgery, and in Aim 2, we will define the mechanisms that underlie the surgery-induced NTS activation.